Biological Threat Agents 101 - PowerPoint Presentation

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Biological Threat Agents 101

Robert J. Leggiadro, MD

Villanova University

Cohen Children’s Medical Center of NY

Donald and Barbara Zucker School of Medicine at Hofstra/Northwell

ACHA Annual Meeting

Washington, DC

May 30, 2018

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Disclosures

Dr. Leggiadro was a full-time employee of Pfizer and Merck

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Learning Objectives

Know the epidemiology, including contagiousness and ease of dissemination, of the more credible biological threat agents.

Identify clinical features of the more credible biological threat agents, including recognition of unusual clinical syndromes or increases above seasonal levels in the incidence of common syndromes or deaths from infectious agents.

Understand management, including reporting, treatment and prevention, of the more credible biological threat agents.

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Clinical and Epidemiological Clues to a BTA Attack

Abrupt onset\Large number of cases “Point-source” outbreak

Occurrence of non-endemic disease

Disease occurring “out of season”

Unusual clinical presentations

No obvious epi risk factors

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Critical Biological Agents

Bacteria

Anthrax

Plague

Tularemia

Viruses

Smallpox

Viral hemorrhagic fever

Toxins

Botulinum toxin

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Anthrax

Bacillus anthracis

, a bacterial zoonosis

Anthrakis, from the Greek word for coal

Cutaneous, inhalational, GI and injectional

clinical forms

Cutaneous most common 2

0

animal contact

No human-human transmission

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Sverdlovsk

Incident at a military microbiology facility

Former Soviet Union, 1979

Grim warning of biologic weapons dangers

Accidental release anthrax spores

At least 79 cases, including 68 deaths

Largest reported inhalational outbreak, occurred within 4 km zone downwind

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Investigation of Bioterrorism-related Anthrax and Interim Guidelines for Clinical Evaluation of Persons with Possible Anthrax CDC. MMWR 2001; 50: 94-8.

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Investigation of Bioterrorism-related Anthrax and Interim Guidelines for Clinical Evaluation of Persons with Possible Anthrax CDC MMWR 2001; 50: 94-8.

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Anthrax Mediastinal Widening

Jernigan JA et al. Emerg Infect Dis 2001; 7:933-44.

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Anthrax Pneumonia

Jernigan JA et al. Emerg Infect Dis 2001; 7:933-44.

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Anthrax Meningitis

Gram stain of cerebrospinal fluid showing B. anthracis. Jernigan JA et al. Emerg Infect Dis 2001; 7:933-44.

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Inhalational Anthrax Management

Ciprofloxacin

and

1 additional antibiotic

e.g. linezolid

or

clindamycin

Cipro, meropenem and linezolid if meningitis has not been ruled out

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Anthrax

Raxibacumab humanized monoclonal antibody directed against protective antigen, a component of the anthrax toxin.

Approved for use together with antibiotics to treat anthrax with systemic illness.

Anthrax Immune Globulin (AIG) CDC IND

Either AIG or raxibacumab antitoxin is indicated in cases of systemic anthrax.

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Inhalational AnthraxPost-exposure ProphylaxisAntibiotics

Ciprofloxacin

Doxycycline

Amoxicillin

Vaccination

Anthrax vaccine adsorbed (AVA)

Inactivated, cell-free product, 3 doses

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Cutaneous Anthrax

Blisters or small bumps may itchSwelling can occur around sorePainless ulcer with black center later (eschar) Face, neck, arms, handswww.cdc.gov/anthrax

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Smallpox

First used as biological weapon over 200 years ago

British troops infected Native Americans

through contaminated blankets

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Smallpox

Responsible for more deaths than any other infectious disease.

18th century Europe; 400,000 deaths/yr, including peasants and monarchs alike.

20th century alone; 1/2 billion deaths.

1949; last case in U.S. (Texas)

Routine immunization in U.S. ended in 1972

Target date for destruction

of known virus stock deferred

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Smallpox:Potential Significance

WHO declared eradication in 1980

Known viral stocks in only 2 labs: U.S. and Russia

? Clandestine stockpiles of virus

Increasing number of

susceptibles

Stable virus, aerosol infectivity,

human-human transmission, high mortality

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Diagnosis of Smallpox

Requires astute diagnostician to distinguish from varicella or erythema multiforme

Tissue culture, variola-specific PCR assay and serologic tests will be performed at CDC reference laboratory

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Smallpox

Lesions on each area at same stage of development; deeply embedded; concentrated on face, extremities.Henderson DA. Emerg Infect Dis 1999; 5: 537-9.

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Chickenpox

Series of crops; superficial; trunk. Henderson DA. Emerg Infect Dis 1999; 5: 537-9.

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Smallpox:Medical Management

Even one confirmed case is an international public health emergency with immediate reporting to public health authorities

Strict isolation with both respiratory and wound isolation

No proven effective antiviral therapy

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New York City Residents Line Up for Vaccinations During a Smallpox Vaccination Campaign, 1947. CDC. MMWR 2003; 52: 933-6.

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Smallpox:Preventive Measures

Vaccination

: vaccinia live virus vaccine

- Protection decreases with time

- Contraindicated if pregnant or

immunosuppressed

All contacts should be STRICTLY quarantined for 16 -17 d post-exposure

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Smallpox Vaccines

Do not contain variola virus

Made from related vaccinia virus

FDA licensed new smallpox vaccine, grown in lab cell culture, ACAM2000 in 2007, which replaced previously licensed vaccine Dryvax

Two additional smallpox vaccines in the Strategic National Stockpile are: WetVax and Imvamune

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Smallpox Vaccines

WetVax liquid formulation live vaccinia virus similar to lyophilized vaccine, Dryvax

ACAM2000 and WetVax by scarification (percutaneous, bifurcated needle)

Imvamune 3

rd

-generation, non-replicating smallpox vaccine for healthy persons AND persons with immunocompromising or pre-existing conditions, e.g., atopic dermatitis (subcutaneous injection)

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Dermatologic Vaccinia Reactions

Progressive vaccinia:

Necrosis in the area of vaccinia

Eczema

vaccinatum

:

Local or generalized spread of vaccinia virus in eczema

Generalized vaccinia:

Skin lesions remote from the vaccination site

Adalja AA et al. N

Engl

J Med 2015; 372: 954-62

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Household Transmission of Vaccinia Virus from Contact with a Military Smallpox Vaccinee—IL and IN, 2007 CDC. MMWR 2007; 56: 478-81

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Smallpox Vaccination and Adverse Reactions CDC. MMWR 2003; 52(RR04): 1-28

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Ring Around the Rosie: Plague Reference

Ring around the rosie (rosy rash of plague)

A pocket full of posies (herbs to ward off smell of the dead)

Ashes! ashes! (cremation and burning victims’ houses)

We all fall down (die)

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Plague

Zoonotic illness (

Yersinia pestis

)

First used as biological weapon

in the 14th century

Tatar force attacking Caffa (Ukraine)

Catapulted bodies of plague victims

into the city

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Plague

Primarily disease of rodents

Transmission to humans: flea bites, direct contact infected body fluids or tissues, or inhalation respiratory droplets (human-human transmission)

1-17 average # cases reported in the U.S. between 2001-2012; median # , 3

Arizona, California, Colorado, New Mexico

Bubonic, septicemic, pneumonic

clinical forms

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Epidemiology of Human Plague in the U.S.

Multiple rodents contribute to the current ecology of plague in the U.S., including:

Ground squirrels

Prairie dogs

Wood rats

Chipmunks

Deer mice

Voles

16

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Reported Cases of Human Plague— United States, 1970--2016

www.cdc.gov/plague

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Human Plague Cases and Deaths United States, 2000-2016

www.cdc.gov/plague

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Reported Plague Cases by Country, 2010-2015

www.cdc.gov/plague

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Plague: Potential Significance

Could be delivered as aerosol

during a biological attack

Has been studied as potential

weapon by both Japan (WWII)

and United States (1950s)

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Pneumonic Plague: Clinical Features

Incubation period of 2-3 days

Initial symptoms are nonspecific:

fever, chills, headache, cough

Later progresses to respiratory

failure and shock

Human-to-human transmission

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Diagnosis of Plague

Gram\Wright-Giemsa\Wayson stain:

- Gram negative coccobacillus

- Bipolar “safety-pin” staining

Pinpoint, grayish, slightly mucoid

colonies after 24 hours on culture

Confirmatory testing at CDC’s

reference laboratory (DFA, PCR)

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Plague Management

Streptomycin, gentamicin

Doxycycline, ciprofloxacin

Post-exposure Prophylaxis

Doxycycline, ciprofloxacin

Pre-exposure Prophylaxis

Killed, whole-cell vaccine no longer available

Droplet precautions for pneumonic plague

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Tularemia

Infection with

Francisella tularensis

Zoonosis

Infectious dose is very low

No human-human transmission

Several forms reflect portal of entry: ulceroglandular, glandular, pneumonia, oropharyngeal, oculoglandular, typhoidal and gastrointestinal

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Tularemia

U.S., 2001-2010

1,208 cases (mean, 126 cases/yr; range, 90-154)

Cases were reported from 47 states

MO, AR, OK, MA, SD, KS; 59% cases

77% cases occurred May through September

Peak arthropod activity/outdoor human activity

Most common males, young and old

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Tularemia

Transmission

Arthropod bites (Summer)

Animal contact (Winter)

Aerosolization (Lawn mowing)

Contaminated water (Europe)

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Reported cases of tularemia—United States, 2001-2010

Tularemia—United States, 2001-2010. CDC. MMWR 2013; 62: 963-6.

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Average incidence of tularemia, by age group and sex—United States, 2001-2010

Tularemia—United States, 2001-2010. CDC. MMWR 2013; 62: 963-6.

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Geographic distribution of reported tularemia cases—CO, NE, SD, and WY, January-September, 2015

Pedati C, et al. Increase in Human Cases of Tularemia—CO, NE, SD, and WY, June-September, 2015. CDC. MMWR 2015; 64:1317-8.

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Tularemia, U.S.- September, 2015

About 125 cases reported annually over the past 20 years

As of 9/30/15, 100 cases reported from CO (43), NE (21), SD (20), and WY (16)

Substantial increase in annual mean # of cases reported in each state during 2004-2014

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Tularemia, U.S.-- 9/30/15

Possible reported exposure routes:

Animal contact n=51

Environmental aerosolizing activities n=49

Arthropod bites n=34

41 patients reported 2 or more exposures

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Tularemia, U.S.--9/30/15

Cause for the increases in 4 states unclear

Possible explanations include:

Increased rainfall promoting vegetation

Pathogen survival

Increased rodent and rabbit populations

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Tularemia

Diagnosis

Serology, Culture, DFA, PCR

Treatment

Aminoglycosides

Ciprofloxacin, doxycycline

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TularemiaBioterrorist Event

Inhalation of aerosol likely route

Pneumonic or typhoidal most likely

clinical manifestations

Postexposure

Doxycycline, ciprofloxacin

Pre-exposure

Live-attenuated vaccine no longer available in the U.S.

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Botulism:Potential Significance

Clostridium botulinum

toxin is one of the most potent compounds known

Clinical forms include infantile, wound, GI, iatrogenic, and inhalational (rare)

Can be aerosolized or used to

sabotage food/water supplies

No human-human transmission

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Botulism:Clinical Features

Estimated toxic dose = .0001

u

g/kg

Incubation period for inhalational

botulism varies from 24-36 hours

Syndrome is the same whether

toxin is ingested or inhaled: afebrile; symmetric, descending paralysis, clear sensorium with bulbar palsies; diplopia, dysarthria, dysphonia, dysphagia

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Diagnosis of Botulism

Clinical presentation may be

confused with Guillain – Barre

or myasthenia gravis

Toxin assay on sera, stool

or “suspect” food

Eight known toxin types: A through H; A (West), B (East), E (Canada, Alaska); E is found almost exclusively in seafood; G does not cause natural human disease

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Botulism:Medical Management

Intensive supportive care

(often for weeks or months)

Equine-derived Heptavalent (A-G) Botulinum Antitoxin (BAT)

Licensed by FDA 2013 and

available exclusively through CDC

No vaccine

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Features Suggesting Deliberate Botulinum Toxin Release

Outbreak of acute flaccid paralysis with prominent bulbar palsies

Outbreak with unusual botulinum toxin type (C,D,F, or G, or E not from aquatic food)

Outbreak with common geographic factor, but without common dietary exposure (suggestive of aerosol attack)

Multiple simultaneous outbreaks without common source

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Viral Hemorrhagic Fever

Arenaviruses

New World

Argentine, Bolivian, Brazilian, Venezuelan

Old World

Lassa Fever

Bunyaviruses

HFRS (Old World Hantavirus)

HPS (New World Hantavirus)

Crimean-Congo HF

Rift Valley Fever

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Viral Hemorrhagic Fever

Filoviruses

Marburg

Ebola

Flaviviruses

Dengue

Yellow Fever

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Viral Hemorrhagic Fever

Geographic Distribution

Ebola, Marburg Africa

Lassa (Old World Arenavirus) West Africa

New World Arenavirus Americas

Yellow Fever Africa, Americas

Dengue Africa, Americas, Asia

Hantavirus Americas, Asia

Rift Valley Fever Africa, Middle East

Crimean-Congo HF Africa,Balkans,ME,Asia

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Viral Hemorrhagic Fever

Vectors

Rodent: Arenavirus, Hantavirus

Tick: Crimean-Congo HF

Mosquito: Rift Valley Fever

Yellow Fever, Dengue

Fruit Bat: Ebola

Marburg

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Viral Hemorrhagic Fever

Clinical Features

Symptoms vary among viruses

Fever, myalgia, prostration

Petechiae, hemorrhage, shock

Neurologic, pulmonary, hepatic involvement

Mortality

Highest in Filoviruses

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Ricin

Ricin toxin extracted from beans of the castor plant; byproduct of castor oil

Found in paints, varnishes, oils

Inhibits protein synthesis

Inhalation, ingestion, injection

CDC Category B threat agent

1978 assassination Bulgarian exile

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References

CDC. Investigation of bioterrorism-related anthrax and interim guidelines for clinical evaluation of persons with possible anthrax.

MMWR

2001; 50: 94-8.

Jernigan JA, et al. Bioterrorism-related inhalational anthrax: The first 10 cases reported in the United States.

Emerg Infect Dis

2001; 7: 933-44.

www.cdc.gov/anthrax

Henderson DA. Smallpox: Clinical and epidemiologic features.

Emerg Infect Dis

1999; 5:537-9.

CDC. Cardiac deaths after a mass smallpox vaccination campaign-New York City, 1947. MMWR 2003; 52: 933-6.

Adalja AA, Toner E, Inglesby TV. Clinical management of potential bioterrorism conditions.

N Engl J Med

2015; 372: 954-62

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References

CDC. Household transmission of vaccinia virus from contact with a military smallpox vaccinee--IL and IN, 2007.

MMWR

2007; 56: 478-81

CDC. Smallpox vaccination and adverse reactions.

MMWR

2003; 52 (RR04): 1-28.

www.cdc.gov/plague

CDC. Tularemia—United States, 2001-2010.

MMWR

2013; 62: 963-6.

Pedati C, et al. Increase in human cases of tularemia—CO, NE, SD, and WY, January-September 2015.

MMWR

2015; 64: 1317-8.

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Self Assessment

Anthrax, plague, and tularemia are all zoonoses. True or False

Known stocks of smallpox virus currently exist in only two labs, one in the United States and one in Russia. True or False

Bodies of plague victims were catapulted into the city during the siege of Caffa in the 14

th

century. True or False

Diagnosis of tularemia pneumonia in an urban setting without a travel history would warrant evaluation of a possible intentional release. True or False

Vaccines are available for anthrax and smallpox. True or False

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Self Assessment

Declared eradicated worldwide in 1980, the report of a single case of smallpox would represent an International Public Health Emergency. True or False

Plague is endemic in the Southwest U.S. True or False

The intentional release of anthrax through contaminated U.S. mail in the Fall of 2001 was an act of bioterrorism. True or False

Antimicrobial therapy is available for anthrax, plague, and tularemia. True or False

Antitoxin therapy is available for botulism through the CDC. True or False

All answers are True